Key result
Participants with DMD exon 2 duplications clinically classified as DMD had a significantly prolonged age at loss of ambulation compared to non-Dup2 DMD controls (median 12.0 vs 10.5 years; HR 0.29).
Why the study?
To describe the phenotypic spectrum of dystrophinopathy in individuals with DMD exon 2 duplications, who may be candidates for targeted therapies restoring dystrophin expression.
Does the presence of DMD exon 2 duplications alter the age at loss of ambulation compared to controls without Dup2 DMD?
Observational (n=684)
Yes
Does the presence of DMD exon 2 duplications alter the age at loss of ambulation compared to controls without Dup2 DMD?
Hazard Ratio: 0.29 (95% CI 0.17–0.51)
Absolute Event Rate: 12% vs 10.5%
p-value: p=<0.001
Patients with DMD exon 2 duplications display a milder disease course with prolonged ambulation compared to controls without Dup2 DMD, providing critical natural history data for interpreting the efficacy of emerging Dup2-targeted therapies.
Informs counseling and trial interpretation now; leaves open IRES activation as a phenotypic modifier.
Background and Objectives To describe the phenotypic spectrum of dystrophinopathy in a large cohort of individuals with DMD exon 2 duplications (Dup2), who may be particularly amenable to therapies directed at restoring expression of either full-length dystrophin or nearly full-length dystrophin through utilization of the DMD exon 5 internal ribosome entry site (IRES). Methods In this retrospective observational study, we analyzed data from large genotype–phenotype databases (the United Dystrophinopathy Project [UDP] and the Italian DMD network) and classified participants into Duchenne muscular dystrophy (DMD), intermediate muscular dystrophy (IMD), or Becker muscular dystrophy (BMD) phenotypes. Log-rank tests for time-to-event variables were used to compare age at loss of ambulation (LOA) in participants with Dup2 vs controls without Dup2 in the UDP database and for comparisons between steroid-treated vs steroid-naive participants with Dup2. Results Among 66 participants with Dup2 (UDP = 40, Italy = 26), 61% were classified as DMD, 9% as IMD, and 30% as BMD. Median age at last observation was 15.4 years (interquartile range 8.79–26.0) and 75% had been on corticosteroids for at least 6 months. Age at LOA differed significantly between participants with Dup2 DMD and historical controls without Dup2 DMD (p < 0.001). Valid spirometry was limited but suggested a delay in the typical age-related decline in forced vital capacity and 24 of 55 participants with adequate cardiac data had cardiomyopathy. Discussion Some patients with Dup2 display a milder disease course than controls without Dup2 DMD, and prolonged ambulation with corticosteroids suggests the potential of IRES activation as a molecular mechanism. As Dup2-targeted therapies reach clinical applications, this information is critical to aid in the interpretation of the efficacy of new treatments.
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A 2021 study conducted an observational in Duchenne muscular dystrophy (DMD) (n=684). DMD exon 2 duplication (Dup2) vs. Non-Dup2 DMD historical controls was evaluated on Age at loss of ambulation (LOA) (HR 0.29, 95% CI 0.17-0.51, p=<0.001). Participants with DMD exon 2 duplications clinically classified as DMD had a significantly prolonged age at loss of ambulation compared to non-Dup2 DMD controls (median 12.0 vs 10.5 years; HR 0.29).
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